Measurements of the radioactivity of the cloud from the accident at Windscale Works (Sellafield, England) in October 1957: data submitted to the International Geophysical Year (IGY; July 1957-December 1958).

A fire in a nuclear reactor at Windscale Works (Sellafield, England) in October 1957 led to an uncontrolled aerial release of radionuclides. At the time of the accident air was sampled at various locations in Europe to monitor atmospheric pollution, and the opportunity was taken to measure the sampling filters for activity concentrations of iodine-131, caesium-137 and polonium-210 at the Harwell research establishment (United Kingdom); when it was not possible to perform measurements at Harwell, original measurement data were supplied. This programme of activity measurements was performed in the context of work by the Advisory Committee on Nuclear Radiation of the International Geophysical Year (IGY; July 1957-December 1958). The International Geophysical Year was an international programme of research into a comprehensive range of geophysical phenomena. The results of this measurement programme were originally reported in Harwell Memorandum AERE-M857 (1961) and this Harwell report is reproduced in this paper because of its historical interest and because it is no longer readily accessible to researchers.

The ups and downs of low-carbohydrate diets in the management of Type 1 diabetes: a review of clinical outcomes.

Dietary management has been a mainstay of care in Type 1 diabetes since before the discovery of insulin when severe carbohydrate restriction was advocated. The use of insulin facilitated re-introduction of carbohydrate into the diet. Current management guidelines focus on a healthy and varied diet with consideration of glycaemic load, protein and fat. As a result of frustration with glycaemic outcomes, low-carbohydrate diets have seen a resurgence in popularity. To date, low-carbohydrate diets have not been well studied in the management of Type 1 diabetes. Studies looking at glycaemic outcomes from low-carbohydrate diets have largely been cross-sectional, without validated dietary data and with a lack of control groups. The participants have been highly motivated self-selected individuals who follow intensive insulin management practices, including frequent blood glucose monitoring and additional insulin corrections with tight glycaemic targets. These confounders limit the ability to determine the extent of the impact of dietary carbohydrate restriction on glycaemic outcomes. Carbohydrate-containing foods including grains, fruit and milk are important sources of nutrients. Hence, low-carbohydrate diets require attention to vitamin and energy intake to avoid micronutrient deficiencies and growth issues. Adherence to restricted diets is challenging and can have an impact on social normalcy. In individuals with Type 1 diabetes, adverse health risks such as diabetic ketoacidosis, hypoglycaemia, dyslipidaemia and glycogen depletion remain clinical concerns. In the present paper, we review studies published to date and provide clinical recommendations for ongoing monitoring and support for individuals who choose to adopt a low-carbohydrate diet. Strategies to optimize postprandial glycaemia without carbohydrate restriction are presented.

Effect of peer support on diabetes distress: a cluster randomized controlled trial.

AIM: To investigate whether peer support would reduce diabetes distress and improve glycaemic control when added to usual diabetes education among adults with Type 2 diabetes in China. METHODS: We conducted a cluster randomized trial involving 400 adults with Type 2 diabetes from eight communities in Nanjing. All participants received usual education for an average of 2 h each month from physicians, certified diabetes educators, dieticians, psychologists and podiatric nurses. Peer support was led by trained peer leaders and included diabetes knowledge- and skills-sharing at least once a month, as well as peer-to-peer communication. The primary outcome was diabetes distress measured using the Diabetes Distress Scale at 12 months. Secondary outcomes included fasting plasma glucose, 2-h postprandial glucose and HbA1c concentration. Outcome data were collected from all participants at baseline, 6 months and 12 months. RESULTS: From 2012 to 2013, there were 200 participants in each study arm at baseline. Compared with the usual education arm, the peer support with usual education arm had greater reductions in regimen-related distress (1.4 ± 0.6 vs 1.2 ± 0.4; P=0.004) and total distress (1.3 ± 0.4 vs 1.2 ± 0.3; P=0.038) at 6 months. At 12 months, the scores for emotional burden (1.2 ± 0.3 vs 1.4 ± 0.6; P=0.002), physician-related distress (1.1 ± 0.3 vs 1.3 ± 0.4; P=0.001) and total scores (1.2 ± 0.3 vs 1.3 ± 0.4; P=0.002) were significantly lower in the peer support with usual education arm than in the usual education arm. Fasting plasma glucose levels were lower in the peer support with usual education arm than in the usual education arm at 6 months (7.5 ± 1.95 vs 8.0 ± 2.2; P=0.044) and 12 months (7.0 ± 2.3 vs 7.6 ± 1.5; P=0.008). CONCLUSIONS: Beyond the benefits of usual education, peer support was effective in reducing diabetes distress for Type 2 diabetes mellitus. (Clinical Trials Registry no: NCT02119572).

Application of neurite orientation dispersion and density imaging (NODDI) to a tau pathology model of Alzheimer's disease.

Increased hyperphosphorylated tau and the formation of intracellular neurofibrillary tangles are associated with the loss of neurons and cognitive decline in Alzheimer's disease, and related neurodegenerative conditions. We applied two diffusion models, diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI), to in vivo diffusion magnetic resonance images (dMRI) of a mouse model of human tauopathy (rTg4510) at 8.5months of age. In grey matter regions with the highest degree of tau burden, microstructural indices provided by both NODDI and DTI discriminated the rTg4510 (TG) animals from wild type (WT) controls; however only the neurite density index (NDI) (the volume fraction that comprises axons or dendrites) from the NODDI model correlated with the histological measurements of the levels of hyperphosphorylated tau protein. Reductions in diffusion directionality were observed when implementing both models in the white matter region of the corpus callosum, with lower fractional anisotropy (DTI) and higher orientation dispersion (NODDI) observed in the TG animals. In comparison to DTI, histological measures of tau pathology were more closely correlated with NODDI parameters in this region. This in vivo dMRI study demonstrates that NODDI identifies potential tissue sources contributing to DTI indices and NODDI may provide greater specificity to pathology in Alzheimer's disease.

Effect of intramuscular interferon beta-1a on gray matter atrophy in relapsing-remitting multiple sclerosis: A retrospective analysis.

BACKGROUND: Changes in gray matter (GM) volume may be a useful measure of tissue loss in multiple sclerosis (MS). OBJECTIVES: To investigate the rate, patterns, and disability correlates of GM volume change in an MS treatment clinical trial. METHODS: Patients (n=140) with relapsing-remitting MS were randomized to intramuscular (IM) interferon (IFN) beta-1a or placebo. Treatment effects on GM fraction (GMF) and white matter (WM) fraction (WMF) changes, differences in rates of GMF and WMF change in year one and two on treatment, and differences in atrophy rates by disease progression status were assessed retrospectively. RESULTS: Significantly less GM atrophy (during year two), but not WM atrophy (at any point), was observed with IM IFN beta-1a compared with placebo. Pseudoatrophy effects were more apparent in WM than in GM; in year one, greater WM volume loss was observed with IM IFN beta-1a than with placebo, whereas GM volume loss was similar between groups. Risk of sustained disability progression was significantly associated with GM, but not WM, atrophy. CONCLUSIONS: These results suggest that GMF change is more meaningful than WMF as a marker of tissue loss and may be useful to augment whole brain atrophy measurements in MS clinical trials.

Ten-year follow-up of the 'minimal MRI lesion' subgroup from the original CHAMPS Multiple Sclerosis Prevention Trial.

BACKGROUND: Patients with clinically isolated syndrome (CIS) and characteristic magnetic resonance imaging (MRI) lesions are at high risk for multiple sclerosis (MS). However, patients with a minimal MRI lesion burden (a low T2-hyperintense [low T2] lesion count) may have borderline formal diagnostic criteria, presenting a clinical management challenge. OBJECTIVE: Compare the 10-year disease progression of patients with low and higher T2 lesion counts treated over most intervals. METHODS: CIS patients from the original CHAMPS MS trial were retrospectively assigned to low-T2 (first quartile; 2-8 lesions) or higher-T2 (second through fourth quartiles; ≥ 9 lesions) groups using baseline T2 lesion counts. The 5- and 10-year open-label extension of CHAMPS (CHAMPIONS) evaluated conversion to clinically definite MS (CDMS), MRI activity, relapses, and disability. RESULTS: The vast majority of patients showed new disease activity by MRI and/or clinical criteria at 10 years (low-T2 86%; higher-T2 98%). Fewer low-T2 than higher-T2 patients developed CDMS (40% vs. 63%; p = 0.013); low-T2 patients also had fewer new brain lesions, less brain volume loss, and less disability progression. CONCLUSION: CIS patients with low T2 lesion counts show continued disease activity. However, all assessments of disease progression over 10 years indicated a significantly less severe disease course for low-T2 patients.

Community Health Workers as Agents of Health Promotion: Analyzing Thailand's Village Health Volunteer Program.

The village health volunteers (VHVs) have been a regular part of Thailand's health system since the 1960s. Despite widespread recognition, little research has been conducted to describe VHV activities, the settings in which VHVs provide help, how the program is administered, and how changing politics and health problems in Thailand have influenced the program. In order to understand the roles and practices of the VHVs, we conducted in-depth semi-structured interviews and focus groups with VHVs, community leaders and members, and public health officials in three semi-urban communities in central Thailand. Using the Social Ecological Framework, we mapped factors that influenced how the VHVs provided support, including governmental oversight, collaboration with public health officials, and community trust. These influences are discussed as "points of consideration," which help to identify the strengths and tensions within the VHV program and best practices in supporting and assessing community health worker efforts.

Complex relation among Health Belief Model components in TB prevention and care.

OBJECTIVES: This study aims to explore the relationships among components of the Health Belief Model, tuberculosis (TB) preventive behavior, and intention of seeking TB care. STUDY DESIGN: Cross section study. METHODS: Using convenience sampling, 1154 rural-to-urban migrant workers were selected between the ages of 18-50 years in six urban areas of three provinces in China. The survey was conducted by individual, face-to-face interviews with a standardized questionnaire. Lisrel 8.7 was used to conduct path analysis. RESULTS: The knowledge and benefits components of the Health Belief Model predicted preventive behaviors: cover nose/mouth when coughing or sneezing (ß = 0.24, 0.33 respectively), evade others' coughs (ß = 0.13, 0.25) and also predicted seeking TB care (ß = 0.27, 0.19). Susceptibility and severity also predicted seeking TB care (ß = 0.12, 0.16). There were also important relationships among model components. Knowledge of TB predicted both susceptibility (ß = 0.32-0.60) and severity (ß = 0.41-0.45). Further, each of susceptibility (ß = 0.30) and severity (ß = 0.41) predicted perceived benefits of preventive care. CONCLUSION: Thus, a path from knowledge, through severity and susceptibility, and then through benefits predicted prevention and TB care seeking behaviors.

[Concepts for the return of secondary genetic findings in medical diagnostics and research]. / Konzepte zur Mitteilung genetischer Zusatzbefunde in der medizinischen Diagnostik und Forschung.

High-throughput sequencing of whole genomes is technically already at a high level and is being discussed as a cost-effective alternative to other targeted, analytical procedures for clinical diagnosis of heritable disorders. On the other hand, with whole genome and whole exome sequencing, there is a high likelihood of uncovering secondary findings not associated with the primary aim of the investigation. This article tries to outline the current scientific and technical status of whole genome and whole exome sequencing and of the national and international recommendations concerning the handling of secondary genetic findings which are already available, above all in the research-related context and less so in the clinical context.

Efficacy of dexmedetomidine compared with midazolam for sedation in adult intensive care patients: a systematic review.

Patients in Intensive Care Unit (ICU) often require sedatives which commonly include midazolam and the more recently developed α2-receptor agonist, dexmedetomidine. It was our aim to compare the sedative and clinical effectiveness of dexmedetomidine vs midazolam in adults admitted to ICU, using an objective appraisal of randomized control trials. Medline, Embase, SCOPUS, Web of Knowledge, Cinhal, the United States National Library of Medicine, and the Cochrane Database of Systematic Reviews were searched using keywords: 'dexmedetomidine', 'midazolam', and 'intensive care'. These were limited to human studies and adults (>18 yr old). Six randomized controlled trials were found and were critically appraised using a standardized appraisal method. Two papers described the time spent by each intervention group within a specified target sedation range and both found no statistically significant difference between midazolam and dexmedetomidine (P=0.18 and P=0.15). A third paper found no statistically significant difference in the length of time that patients were sedated within a target zone (P=0.445). Two additional pilot studies did not report P values as they were insufficiently statistically powered. A final paper found that, of the eight occasions measured, patients on dexmedetomidine were more often within the target sedation range than patients on midazolam. The sedative benefits of dexmedetomidine vs midazolam remain inconclusive. While some secondary outcomes showed clinical effectiveness of dexmedetomidine, more research is needed to validate the findings of these studies.

Genetic and molecular alterations in pancreatic cancer: implications for personalized medicine.

Recent advances in human genomics and biotechnologies have profound impacts on medical research and clinical practice. Individual genomic information, including DNA sequences and gene expression profiles, can be used for prediction, prevention, diagnosis, and treatment for many complex diseases. Personalized medicine attempts to tailor medical care to individual patients by incorporating their genomic information. In a case of pancreatic cancer, the fourth leading cause of cancer death in the United States, alteration in many genes as well as molecular profiles in blood, pancreas tissue, and pancreas juice has recently been discovered to be closely associated with tumorigenesis or prognosis of the cancer. This review aims to summarize recent advances of important genes, proteins, and microRNAs that play a critical role in the pathogenesis of pancreatic cancer, and to provide implications for personalized medicine in pancreatic cancer.

Evidence that a locus for familial psoriasis maps to chromosome 4q.

Psoriasis is an inflammatory skin disease that affects 2% of the population. It is characterised by red, scaly skin patches which are usually found on the scalp, elbows and knees, and may be associated with severe arthropathy. The lesions are caused by abnormal keratinocyte proliferation, and infiltration of inflammatory cells into the dermis and epidermis. The usual age of onset of psoriasis is between 15 and 30 years, although it can present at any age. Psoriasis is recognised to have a large genetic component. Twin studies show the concordance in monozygotic twins to be between 65-70%, compared to between 15-20% in dizygotic twins. Family studies estimate the risk to first degree relatives at between 8-23%. However, there are also several environmental factors, including streptococcal infection and stress, that affect the onset and presentation of the disease. The mode of inheritance of psoriasis is unclear. We conducted a genome-wide scan to search for psoriasis susceptibility loci in a single large multiplex family. Parametric linkage analysis indicated that a susceptibility locus for familial psoriasis was located on chromosome 4q. Investigation of this locus in five further multiplex families using both parametric and non-parametric methods gave significant localisation to chromosome 4q. The maximum total pairwise lod score obtained was 3.03 with the microsatellite marker D4S1535 at theta = 0.08. Non-parametric multipoint analysis with GENEHUNTER- demonstrated significant excess allele sharing, with a P value of 0.0026, at the same locus.

The Grb2 binding domain of mSos1 is not required for downstream signal transduction.

Cellular Ras proteins are activated primarily by specific guanine-nucleotide releasing factors such as the Son of Sevenless (Sos) proteins. This activation event is thought to occur in response to plasma membrane localization of a complex containing Sos and a small adapter protein Grb2. We have isolated a dominant mutant allele of mSos1 which transforms Rat1 cells, yet is no longer able to bind Grb2. Biochemical experiments reveal that the subcellular distribution of this truncated Sos protein is not altered with respect to the wild type Sos protein. These data argue against a role for Grb2 in the direct recruitment of Sos proteins to the plasma membrane and suggest that Grb2 may function to overcome negative regulation of Sos by its C terminus.

Genealogies of mouse inbred strains.

The mouse is a prime organism of choice for modelling human disease. Over 450 inbred strains of mice have been described, providing a wealth of different genotypes and phenotypes for genetic and other studies. As new strains are generated and others become extinct, it is useful to review periodically what strains are available and how they are related to each other, particularly in the light of available DNA polymorphism data from microsatellite and other markers. We describe the origins and relationships of inbred mouse strains, 90 years after the generation of the first inbred strain. Given the large collection of inbred strains available, and that published information on these strains is incomplete, we propose that all genealogical and genetic data on inbred strains be submitted to a common electronic database to ensure this valuable information resource is preserved and used efficiently.

A systematic, genome-wide, phenotype-driven mutagenesis programme for gene function studies in the mouse.

As the human genome project approaches completion, the challenge for mammalian geneticists is to develop approaches for the systematic determination of mammalian gene function. Mouse mutagenesis will be a key element of studies of gene function. Phenotype-driven approaches using the chemical mutagen ethylnitrosourea (ENU) represent a potentially efficient route for the generation of large numbers of mutant mice that can be screened for novel phenotypes. The advantage of this approach is that, in assessing gene function, no a priori assumptions are made about the genes involved in any pathway. Phenotype-driven mutagenesis is thus an effective method for the identification of novel genes and pathways. We have undertaken a genome-wide, phenotype-driven screen for dominant mutations in the mouse. We generated and screened over 26,000 mice, and recovered some 500 new mouse mutants. Our work, along with the programme reported in the accompanying paper, has led to a substantial increase in the mouse mutant resource and represents a first step towards systematic studies of gene function in mammalian genetics.

Effect of preoperative chemotherapy on the outcome of women with operable breast cancer.

PURPOSE: To determine, in women with primary operable breast cancer, if preoperative doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan; AC) therapy yields a better outcome than postoperative AC therapy, if a relationship exists between outcome and tumor response to preoperative chemotherapy, and if such therapy results in the performance of more lumpectomies. PATIENTS AND METHODS: Women (1,523) enrolled onto National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 were randomly assigned to preoperative or postoperative AC therapy. Clinical tumor response to preoperative therapy was graded as complete (cCR), partial (cPR), or no response (cNR). Tumors with a cCR were further categorized as either pathologic complete response (pCR) or invasive cells (pINV). Disease-free survival (DFS), distant disease-free survival (DDFS), and survival were estimated through 5 years and compared between treatment groups. In the preoperative arm, proportional-hazards models were used to investigate the relationship between outcome and tumor response. RESULTS: There was no significant difference in DFS, DDFS, or survival (P = .99, .70, and .83, respectively) among patients in either group. More patients treated preoperatively than postoperatively underwent lumpectomy and radiation therapy (67.8% v 59.8%, respectively). Rates of ipsilateral breast tumor recurrence (IBTR) after lumpectomy were similar in both groups (7.9% and 5.8%, respectively; P = .23). Outcome was better in women whose tumors showed a pCR than in those with a pINV, cPR, or cNR (relapse-free survival [RFS] rates, 85.7%, 76.9%, 68.1%, and 63.9%, respectively; P < .0001), even when baseline prognostic variables were controlled. When prognostic models were compared for each treatment group, the preoperative model, which included breast tumor response as a variable, discriminated outcome among patients to about the same degree as the postoperative model. CONCLUSION: Preoperative chemotherapy is as effective as postoperative chemotherapy, permits more lumpectomies, is appropriate for the treatment of certain patients with stages I and II disease, and can be used to study breast cancer biology. Tumor response to preoperative chemotherapy correlates with outcome and could be a surrogate for evaluating the effect of chemotherapy on micrometastases; however, knowledge of such a response provided little prognostic information beyond that which resulted from postoperative therapy.

The effect of citalopram treatment on amyloid-ß precursor protein processing and oxidative stress in human hNSC-derived neurons.

Selective Serotonin Reuptake Inhibitors (SSRIs) may hold therapeutic benefits for people with Alzheimer's disease (AD). SSRIs may perturb AD progression, or the conversion from MCI to AD, via increased neurogenesis, reduced oxidative stress and/or favourable Amyloid-ß Precursor Protein (AßPP) processing. This study used iPSC derived cortical neuronal cells carrying 3 different PSEN1 mutations, to investigate the effect of treatment with the SSRI, Citalopram on AßPP processing and oxidative stress. Control and PSEN1 mutation (L286V, A246E, M146L) iPSC-derived neurons were treated with Citalopram for 45 days. ADAM10 activity, AßPP processing and Aß generation was measured in addition to cellular redox status. Citalopram treatment reduced the Aß1-42:40 ratio in control but not in fAD PSEN1 cells. ADAM10 activity was increased with Citalopram treatments in fAD PSEN1 cell lines, which was also seen for sAßPPα secretion. Lower superoxide generation in fAD PSEN1 cells following Citalopram treatment was identified, although there was no effect on end markers of oxidative stress. Treatment with Citalopram appears to have little effect on Aß generation in fADPSEN1 cells, but our findings suggest that treatment can significantly increase non-amyloidogenic AßPP processing and reduce oxidative stress. These changes may explain why SSRIs appear most effective in the prodromal period of the disease progression, as opposed to reducing established AD pathology. Further investigation of specific pathways conferring the beneficial effects of SSRIs treatment are warranted.

A method to determine the available UV-C dose for the decontamination of filtering facepiece respirators.

AIMS: To develop a method to assess model-specific parameters for ultraviolet-C (UV-C, 254 nm) decontamination of filtering facepiece respirators (FFRs). METHODS AND RESULTS: UV-C transmittance was quantified for the distinct composite layers of six N95 FFR models and used to calculate model-specific α-values, the percentage of the surface UV-C irradiance available for the internal filtering medium (IFM). Circular coupons, excised from the FFRs, were exposed to aerosolized particles containing MS2 coliphage and treated with IFM-specific UV-C doses ranging from 38 to 4707 J m(-2). Models exposed to a minimum IFM dose of 1000 J m(-2) demonstrated at least a 3 log reduction (LR) in viable MS2. Model-specific exposure times to achieve this IFM dose ranged from 2 to 266 min. CONCLUSIONS: UV-C transmits into and through FFR materials. LR of MS2 was a function of model-specific IFM UV-C doses. SIGNIFICANCE AND IMPACT OF THE STUDY: Filtering facepiece respirators are in high demand during infectious disease outbreaks, potentially leading to supply shortages. Reuse of disposable FFRs after decontamination has been discussed as a possible remediation strategy, but to date lacks supporting scientific evidence. The methods described here can be used to assess the likelihood that UV-C decontamination will be successful for specific FFR models.

Patterning Chronic Active Demyelination in Slowly Expanding/Evolving White Matter MS Lesions.

BACKGROUND AND PURPOSE: Slowly expanding/evolving lesions measured by conventional T1-weighted/T2-weighted brain MR imaging may contribute to progressive disability accumulation in MS. We evaluated the longitudinal change in myelin and axonal tissue integrity in white matter slowly expanding/evolving lesions by means of the magnetization transfer ratio and DTI radial diffusivity. MATERIALS AND METHODS: Slowly expanding/evolving lesions were detected within the Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of BIIB033 in Participants With Relapsing Forms of Multiple Sclerosis When Used Concurrently With Avonex (SYNERGY) Phase 2 clinical trial dataset (NCT01864148), comprising patients with relapsing-remitting and secondary-progressive MS (n = 299) with T1-weighted/T2-weighted MR imaging at all trial time points (baseline to week 72). RESULTS: Compared with non-slowly expanding/evolving lesions (areas not classified as slowly expanding/evolving lesion) of baseline nonenhancing T2 lesions, slowly expanding/evolving lesions had a lower normalized magnetization transfer ratio and greater DTI radial diffusivity, both in patients with relapsing-remitting MS (n = 242) and secondary-progressive MS (n = 57, P < .001 for all). Although the changes with time in both the normalized magnetization transfer ratio and DTI radial diffusivity between slowly expanding/evolving lesions and non-slowly expanding/evolving lesions were positively correlated (P < .001), a decrease in the normalized magnetization transfer ratio and a greater increase in DTI radial diffusivity were observed in slowly expanding/evolving lesions versus non-slowly expanding/evolving lesions from baseline to week 72 in relapsing-remitting MS and secondary-progressive MS (P < .001 for all). CONCLUSIONS: Patterns of longitudinal change in the normalized magnetization transfer ratio and DTI radial diffusivity in slowly expanding/evolving lesions were consistent with progressive demyelination and tissue loss, as seen in smoldering white matter MS plaques.